ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo

David R. Gibb, Mohey El Shikh, Dae Joong Kang, Warren J. Rowe, Rania El Sayed, Joanna Cichy, Hideo Yagita, John G. Tew, Peter J. Dempsey, Howard C. Crawford, Daniel H. Conrad

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10-/-mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell-specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer.

Original languageEnglish (US)
Pages (from-to)623-635
Number of pages13
JournalJournal of Experimental Medicine
Volume207
Issue number3
DOIs
StatePublished - Mar 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Gibb, D. R., El Shikh, M., Kang, D. J., Rowe, W. J., El Sayed, R., Cichy, J., Yagita, H., Tew, J. G., Dempsey, P. J., Crawford, H. C., & Conrad, D. H. (2010). ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. Journal of Experimental Medicine, 207(3), 623-635. https://doi.org/10.1084/jem.20091990